Pregelatinized starch in a controlled release formulation

ABSTRACT

The present invention concerns the use of pregelatinized starch to prevent dose-dumping from a hydrophilic controlled release formulation. It also concerns a hydrophilic controlled release formulation, more in particular a hydrophilic controlled release matrix formulation, and solid dosage forms prepared therefrom, preferably for once daily oral administration. The hydrophilic controlled release formulation comprises pregelatinized starch, one or more active ingredients, one or more viscous hydrophilic polymers and optionally pharmaceutically acceptable formulating agents. Preferred hydrophilic polymers include hydroxypropyl cellulose and hydroxypropyl methylcellulose.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. 371 ofApplication No. PCT/EP00/02620 filed Mar. 24, 2000, which claimspriority from EP 99201018.1, filed Mar. 31, 1999.

The present invention concerns the use of pregelatinized starch toprevent dose-dumping from a hydrophilic controlled release formulation.It also concerns a hydrophilic controlled release formulation, more inparticular a hydrophilic controlled release matrix formulation, andsolid dosage forms prepared therefrom, preferably for once daily oraladministration. The hydrophilic controlled release formulation comprisespregelatinized starch, one or more active ingredients, one or moreviscous hydrophilic polymers and optionally pharmaceutically acceptableformulating agents. Preferred hydrophilic polymers include hydroxypropylcellulose and hydroxypropyl methylcellulose.

WO 96/14070 discloses an extended release formulation for oraladministration comprising cisapride-(L)-tartrate as the activeingredient embedded in a matrix of two hydrophilic viscous polymers, inparticular hydroxypropyl cellulose and hydroxypropyl methylcellulose.These hydrophilic polymers swell upon contact with water, therebyforming a gellayer from which the active ingredient is graduallyreleased.

WO 97/24109 describes bioadhesive pharmaceutical compositions and soliddosage forms prepared therefrom, which comprise a pharmaceuticallyeffective amount of an active ingredient, from 80% to 98% (w/w)pregelatinized starch incorporated in the composition as a bioadhesivepolymer, and from 1% to 10% (w/w) of a hydrophilic matrix formingpolymer. Said dosage forms have a regular and prolonged release patternfor a locally acting ingredient or also for a systemically acting drug,and they are suitable for oral, nasal, rectal and vaginaladministration.

EP 0299877 concerns a tablet containing salbutamol or a derivativethereof homogeneously dispersed in a hydrophilic matrix comprising atleast one high molecular weight cellulose hydrocolloid as swellingagent, in particular hydroxypropyl methylcellulose 15 Pa.s, and adiluent, in which said diluent comprises one intrinsic diluent and onethickening diluent, in particular pregelatinized maize starch.

EP 0280613 describes a tablet comprising a homogeneous dispersion ofdihydroergotamine or one of its derivatives in a water-soluble matrixcomprising one or more water-soluble polymeric substances, in particularhydroxypropyl methylcellulose, and a diluent comprising at least onestarch derivative, in particular pregelatinized maize starch.

EP 0477061 claims a sustained-release tablet comprising isosorbide5-mononitrate in homogeneous dispersion in a hydrophilic matrix based onat least one swelling component, in particular hydroxypropylmethylcellulose, and at least one diluent. The latter contains at leastone intrinsic diluent and one thickening diluent chosen from polymerssuch as starch and starch derivatives.

GB 2,195,893 describes a sustained release pharmaceutical compositioncomprising a pharmacologically active agent in admixture with a)microcristalline cellulose and b) hydroxypropyl methylcellulose whereinthe weight ratio of a) to b) is at least 1 to 1, with the proviso thatwhen the active ingredient is other than acetyl salicylic acid in freeform or salt form, the active agent is also in admixture withpregelatinized starch.

WO 97/04752 describes a pharmaceutical composition for oraladministration of conjugated estrogens. Said conjugated estrogens arecoated onto one or more organic excipients comprising hydroxypropylmethylcellulose and pregelatinized starch, the latter being present as asuitable binder.

Controlled release pharmaceutical preparations regulate the release ofthe incorporated active ingredient or ingredients over time and comprisepreparations with a prolonged, a sustained, a slow, a continuous, aretarded or an extended release, so they accomplish therapeutic orconvenience objectives not offered by conventional dosage forms such assolutions or promptly dissolving dosage forms. Controlled release ofactive ingredient(s) allows to simplify the patient's posological schemeby reducing the amount of recommended daily intakes and improvespatient's compliance. One should not underestimate the positivepsychological effect towards the patient of a once daily intake insteadof a twice or multiple daily intake.

A controlled release of active ingredient(s) from a pharmaceuticalpreparation may be accomplished by homogeneously embedding said activeingredient(s) in a hydrophilic matrix, being a soluble, partiallysoluble or insoluble network of viscous, hydrophilic polymers, heldtogether by physical or chemical entanglements, by ionic or crystallineinteractions, by complex formation, by hydrogen bonds or van der Waalsforces. Said hydrophilic matrix swells upon contact with water, therebycreating a protective gellayer from which the active ingredient(s) is(are) slowly, gradually, continuously released in time either bydiffusion through the polymeric network, by erosion of the gellayer, bydissolution of the polymer, or by a combination of said releasemechanisms. Commonly used hydrophilic polymers for the preparation ofcontrolled release matrices comprise polysaccharides, polyacrylates, andpolyalkylene oxides.

An effective oral controlled release preparation, especially a once ortwice daily controlled release preparation, preferably retains itspharmacokinetic release profile along its way through thegastro-intestinal tract so as to avoid undesirable fluctuations in drugplasma concentrations or complete dose-dumping. This implies that acontrolled release preparation preferably has to provide a controlledrelease profile and in particular has to avoid dose-dumping in media ofvarying ionic strength since the gastro-intestinal luminal contentexhibits varying values of ionic strength in different regions of thegastro-intestinal tract.

When administering a controlled release preparation to patients in thefed state, food related dose-dumping may be encountered. The problem offood related dose-dumping in fed patients can be attributed to a lot offactors. One of these factors is surely the mechanical forces that areexerted by the stomach on its content and thus on an ingestedpreparation. Another factor appears to be the ionic strength of thegastro-intestinal juices. Since the ionic strength values encountered inthe gastro-intestinal tract vary not only with the region of the tract,but also with the intake of food, a controlled release formulationpreferably also has to provide a controlled release profile and inparticular has to avoid dose-dumping regardless whether the patient isin fasted or fed conditions. The ionic strength of the gastro-intestinalfluids may range from about 0.01 to about 0.2 (Johnson et al., 1993,Int. J. Pharm., 90, 151-159).

The ionic strength, mostly represented by the symbol μ (sometimes I), isa characteristic of a solution and is defined as$\mu = {{1/2}{\sum\limits_{i}\quad {c_{i} \cdot Z_{i}^{2}}}}$

wherein c_(i) is the molar concentration of the ith ion, Z_(i) is itscharge, and the summation extends over all the ions in solution (Martin,A., 1993, Physical Pharmacy, Williams & Wilkins, pp 134-135). The ionicstrength is thus a property of the solution and not of any particularion in the solution. The ionic strength is known to constitute a goodmeasure of the non-ideality imposed by all the ions of a solution on theions produced by a given electrolyte in the solution.

The effect of the ionic strength of the surrounding medium on thedisintegration, gelation and viscosity of hydrophilic matrices isdescribed in the literature.

Mitchell et al. (Pharmaceutical Technology. Controlled drug release,vol.2, by Wells, J. I., Rubinstein, M. H. (Eds.), Ellis Horwood Limited,pp. 23-33, 1991) disclose the effect of electrolytes on thedisintegration and gelation of hydroxypropyl methylcellulose (HPMC) K15Mmatrix tablets. At low ionic strength of the surrounding medium, HPMCmatrices are unaffected by electrolytes and hydration occurs to producean intact gel layer. At intermediate ionic strength however, thematrices lose shape and integrity, and they disintegrate rapidly. Thetablets cease to act as controlled release matrices because gelation isprevented by a reduction in hydration in case of increased soluteconcentrations in the surrounding medium. Thus, electrolytes present inthe surrounding medium can modify the release profile of drugs from HPMCmatrices. The drugs themselves may also influence the hydration, andthus the gelation of HPMC. Therefore, drugs may play an active role indetermining their own release (Mitchell et al., Int. J. Pharm., 1993,100, 165-173). Consequently, the incorporation of drugs in HPMC matricesmay result in unpredictable dissolution profiles and hence unpredictabletherapeutic efficiency of the dosage forms.

The swelling behaviour of xanthan gum matrix tablets in sodium chloridesolutions of different ionic strength is described in Int. J. Pharm.,1995, 120, 63-72. Within the range of physiological ionic strength, theswelling of the xanthan gum tablets shows a reciprocal relationship withsalt concentration.

Unexpectedly, it has been found that the impairing or even destroyingeffect of the ionic strength of a release medium on the controlledrelease profile of a hydrophilic matrix formulation can be countered byadding pregelatinized starch to the formulation. Said impairing effectof ionic strength on the controlled release profile of a hydrophilicmatrix formulation may be attributed, as indicated hereinbefore, tochanges in the hydration of the viscous hydrophilic matrix polymers.Said matrix polymers have to compete for hydration water with thesolutes making up the ionic strength of the release medium.Consequently, the polymers may not hydrate to such extent as to ensureformation of a sufficiently integer matrix with acceptable resistance todisintegration. Hydration of the matrix polymers may largely or evencompletely be suppressed so that the matrix disintegrates almostimmediately, e.g. within a time interval of 15 min after administrationin the release medium. By incorporating pregelatinized starch in theformulation, the controlled release of active ingredient(s) from ahydrophilic controlled release formulation can be safeguarded ormaintained in release media of changing ionic strength, in particular inrelease media with increasing ionic strength, more in particular inrelease media with ionic strength values ranging up to 0.4, even more inparticular in release media with ionic strength values encountered inphysiological conditions, i.e. along the entire gastro-intestinal tractboth in fasted as well as in fed conditions, and most in particular inrelease media with ionic strength values ranging from about 0.01 toabout 0.2.

Thus, the present invention relates to the use of pregelatinized starchin a hydrophilic controlled release formulation comprising one or moreactive ingredients and one or more viscous hydrophilic polymers tocounter the impairing effect of ionic strength of the release medium onthe controlled release of active ingredient(s) from said formulation orthe use of pregelatinized starch in a hydrophilic controlled releaseformulation comprising one or more active ingredients and one or moreviscous hydrophilic polymers to maintain a controlled release of activeingredient(s) from said formulation in release media with changing ionicstrength, in particular in release media with increasing ionic strength,more in particular in release media with ionic strength values rangingup to 0.4, even more in particular in release media with ionic strengthvalues encountered in physiological conditions, i.e. along the entiregastro-intestinal tract both in fasted as well as in fed conditions, andmost in particular in release media with ionic strength values rangingfrom about 0.01 to about 0.2. This invention also includes the use ofpregelatinized starch in a hydrophilic controlled release formulationcomprising one or more active ingredients and one or more viscoushydrophilic polymers to prevent dose-dumping from said formulation alongthe gastro-intestinal tract both in fasted as well as in fed conditions,more in particular to prevent food-related dose-dumping.

The term “release medium” as used hereinbefore or hereinafterencompasses all kinds of liquid media wherein the release of activeingredient(s) from the hydrophilic controlled release formulation canoccur, i.e. for example in in vitro dissolution media, but also in bodyfluids, more in particular in the gastro-intestinal fluids.

The term “to maintain a controlled release of active ingredient(s) fromthe formulation” indicates that the active ingredient(s) is (are)slowly, gradually, continuously, prolonged, sustained or extendedreleased in time from the formulation. In particular, the term “acontrolled release of active ingredient(s) from the formulation”indicates that the formulation does not release the active ingredientimmediately after oral dosing and that the formulation allows areduction in dosage frequency, following the definition for extendedrelease, interchangeable with controlled release, according to theUnited States Pharmacopeia 24, p 2059. A controlled release, usedsynonymously with prolonged action, sustained release, or extendedrelease, dosage form is therein described as a dosage form that allowsat least a two-fold reduction in dosing frequency or a significantincrease in patient compliance or therapeutic performance as compared tothat presented as a conventional dosage form (e.g. as a solution or aprompt drug-releasing, conventional solid dosage form).

The term “dose-dumping” is well known by a person skilled in the art anddefines a sudden release of a major part or all of the activeingredient(s) incorporated in a formulation intended to be used as acontrolled release formulation. Instead of a release spread over anextended period of time, the whole dose or at least a major part thereofis released within a short period of time. This may cause seriousadverse effects or even death depending on the active ingredient andpotency thereof.

The present invention also relates to a hydrophilic controlled releaseformulation comprising pregelatinized starch, one or more activeingredients, one or more viscous hydrophilic polymers and optionallypharmaceutically acceptable formulating agents characterized in that thepregelatinized starch enables the formulation to maintain a controlledrelease of the incorporated active ingredient(s) in release media withchanging ionic strength, in particular in release media with increasingionic strength, more in particular in release media with ionic strengthvalues ranging up to 0.4, even more in particular in release media withionic strength values encountered in physiological conditions, i.e.along the entire gastro-intestinal tract both in fasted as well as infed conditions, and most in particular in release media with ionicstrength values ranging from about 0.01 to about 0.2. The invention alsoconcerns a hydrophilic controlled release formulation comprisingpregelatinized starch, one or more active ingredients, one or moreviscous hydrophilic polymers and optionally pharmaceutically acceptableformulating agents characterized in that the pregelatinized starchprevents dose-dumping from said formulation along the gastro-intestinaltract both in fasted as well as in fed conditions, more in particularthe pregelatinized starch prevents food-related dose-dumping.

The formulation according to the present invention is particularlyuseful for administering one or more active ingredients

(a) with a short half-life, in the order of 4 to 8 hours or less, whichhave to be taken in divided doses during the day when administered in aconventional preparation; or

(b) with a narrow therapeutic index; or

(c) with sufficient absorption over the entire gastro-intestinal tract;or

(d) with a relatively small therapeutically effective dose.

Suitable active ingredients are those which exert a local physiologicaleffect, as well as those which exert a systemic effect, after oraladministration. Examples thereof are:

analgesic and anti-inflammatory drugs (NSAIDs, fentanyl, indomethacin,ibuprofen, ketoprofen, nabumetone, paracetamol, piroxicam, tramadol,COX-2 inhibitors such as celecoxib and rofecoxib);

anti-arrhythmic drugs (procainamide, quinidine, verapamil);

antibacterial and antiprotozoal agents (amoxicillin, ampicillin,benzathine penicillin, benzylpenicillin, cefaclor, cefadroxil,cefprozil, cefuroxime axetil, cephalexin, chloramphenicol, chloroquine,ciprofloxacin, clarithromycin, clavulanic acid, clindamycin,doxyxycline, erythromycin, flucloxacillin sodium, halofantrine,isoniazid, kanamycin sulphate, lincomycin, mefloquine, minocycline,nafcillin sodium, nalidixic acid, neomycin, nortloxacin, ofloxacin,oxacillin, phenoxymethyl-penicillin potassium,pyrimethamine-sulfadoxime, streptomycin);

anti-coagulants (warfarin);

antidepressants. (amitriptyline, amoxapine, butriptyline, clomipramine,desipramine, dothiepin, doxepin, fluoxetine, reboxetine, amineptine,selegiline, gepirone, imipramine, lithium carbonate, mianserin,milnacipran, nortriptyline, paroxetine, sertraline;3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one);

anti-diabetic drugs (glibenclamide, metformin);

anti-epileptic drugs (carbamazepine, clonazepam, ethosuximide,gabapentin, lamotrigine, levetiracetam, phenobarbitone, phenytoin,primidone, tiagabine, topiramate, valpromide, vigabatrin);

antifungal agents (amphotericin, clotrimazole, econazole, fluconazole,flucytosine, griseofulvin, itraconazole, ketoconazole, miconazolenitrate, nystatin, terbinafine, voriconazole);

antihistamines (astemizole, cinnarizine, cyproheptadine,decarboethoxyloratadine, fexofenadine, flunarizine, levocabastine,loratadine, norastemizole, oxatomide, promethazine, terfenadine);

anti-hypertensive drugs (captopril, enalapril, ketanserin, lisinopril,minoxidil, prazosin, ramipril, reserpine, terazosin);

anti-muscarinic agents (atropine sulphate, hyoscine);

antineoplastic agents and antimetabolites (platinum compounds, such ascisplatin, carboplatin; taxanes, such as paclitaxel, docetaxel; tecans,such as camptothecin, irinotecan, topotecan; vinca alkaloids, such asvinblastine, vindecine, vincristine, vinorelbine; nucleoside derivativesand folic acid antagonists such as 5-fluorouracil, capecitabine,gemcitabine, mercaptopurine, thioguanine, cladribine, methotrexate;alkylating agents, such as the nitrogen mustards, e.g. cyclophosphamide,chlorambucil, chiormethine, iphosphamide, melphalan, or thenitrosoureas, e.g. carmustine, lomustine, or other alkylating agents,e.g. busulphan, dacarbazine, procarbazine, thiotepa; antibiotics, suchas daunorubicin, doxorubicin, idarubicin, epirubicin, bleomycin,dactinomycin, mitomycin; HER 2antibody, such as trastuzumab;podophyllotoxin derivatives, such as etoposide, teniposide; famesyltransferase inhibitors; anthrachinon derivatives, such as mitoxantron);

anti-migraine drugs (alniditan, naratriptan, sumatriptan);

anti-Parkinsonian drugs (bromocryptine mesylate, levodopa, selegiline);

antipsychotic, hypnotic and sedating agents (alprazolam, buspirone,chlordiazepoxide, chlorpromazine, clozapine, diazepam, flupenthixol,fluphenazine, flurazepam, 9-hydroxyrisperidone, lorazepam, mazapertine,olanzapine, oxazepam, pimozide, pipamperone, piracetam, promazine,risperidone, selfotel, seroquel, sertindole, sulpiride, temazepam,thiothixene, triazolam, trifluperidol, ziprasidone, zolpidem);

anti-stroke agents (lubeluzole, lubeluzole oxide, riluzole, aptiganel,eliprodil, remacemide);

antitussive (dextromethorphan, laevodropropizine);

antivirals (acyclovir, ganciclovir, loviride, tivirapine, zidovudine,lamivudine, zidovudine+lamivudine, didanosine, zalcitabine, stavudine,abacavir, lopinavir, amprenavir, nevirapine, efavirenz, delavirdine,indinavir, nelfinavir, ritonavir, saquinavir, adefovir, hydroxyurea);

beta-adrenoceptor blocking agents (atenolol, carvedilol, metoprolol,nebivolol, propanolol);

cardiac inotropic agents (amrinone, digitoxin, digoxin, milrinone);

corticosteroids (beclomethasone dipropionate, betamethasone, budesonide,dexamethasone, hydrocortisone, methylprednisolone, prednisolone,prednisone, triamcinolone);

disinfectants (chlorhexidine);

diuretics (acetazolamide, frusemide, hydrochlorothiazide, isosorbide);

enzymes;

essential oils (anethole, anise oil, caraway, cardamom, cassia oil,cineole, cinnamon oil, clove oil, coriander oil, dementholised mint oil,dill oil, eucalyptus oil, eugenol, ginger, lemon oil, mustard oil,neroli oil, nutmeg oil, orange oil, peppermint, sage, spearmint,terpineol, thyme);

gastro-intestinal agents (cimetidine, cisapride, clebopride,diphenoxylate, domperidone, famotidine, lansoprazole, loperamide,loperamide oxide, mesalazine, metoclopramide, mosapride, nizatidine,norcisapride, olsalazine, omeprazole, pantoprazole, perprazole,prucalopride, rabeprazole, ranitidine, ridogrel, sulphasalazine);

haemostatics (aminocaproic acid);

lipid regulating agents (atorvastatin, lovastatin, pravastatin,probucol, simvastatin);

local anaesthetics (benzocaine, lignocaine);

opioid analgesics (buprenorphine, codeine, dextromoramide,dihydrocodeine, hydrocodone, oxycodone, morphine);

parasympathomimetics and anti-dementia drugs (AIT-082, eptastigmine,galanthamine, metrifonate, milameline, neostigmine, physostigmine,tacrine, donepezil, rivastigmine, sabcomeline, talsaclidine, xanomeline,memantine, lazabemide);

peptides and proteins (antibodies, becaplermin, cyclosporine,erythropoietin, immunoglobulins, insuline);

sex hormones (oestrogens: conjugated oestrogens, ethinyloestradiol,mestranol, oestradiol, oestriol, oestrone; progestogens; chlormadinoneacetate, cyproterone acetate, 17-deacetyl norgestimate, desogestrel,dienogest, dydrogesterone, ethynodiol diacetate, gestodene, 3-ketodesogestrel, levonorgestrel, lynestrenol, medroxy-progesterone acetate,megestrol, norethindrone, norethindrone acetate, norethisterone,norethisterone acetate, norethynodrel, norgestimate, norgestrel,norgestrienone, progesterone, quingestanol acetate);

stimulating agents (sildenafil);

vasodilators (amlodipine, buflomedil, amyl nitrite, diltiazem,dipyridamole, glyceryl trinitrate, isosorbide dinitrate, lidoflazine,molsidomine, nicardipine, nifedipine, oxpentifylline, pentaerythritoltetranitrate);

their N-oxides, their pharmaceutically acceptable acid or base additionsalts and their stereochemically isomeric forms.

Pharmaceutically acceptable acid addition salts comprise the acidaddition salt forms which can conveniently be obtained by treating thebase form of the active ingredient with appropriate organic andanorganic acids.

Active ingredients containing an acidic proton may be converted intotheir non-toxic metal or amine addition salt forms by treatment withappropriate organic and inorganic bases.

The term addition salt also comprises the hydrates and solvent additionforms which the active ingredients are able to form. Examples of suchforms are e.g. hydrates, alcoholates and the like.

The N-oxide forms of the active ingredients comprise those activeingredients wherein one or several nitrogen atoms are oxidized to theso-called N-oxide.

The term “stereochemically isomeric forms” defines all the possiblestereoisomeric forms which the active ingredients may possess. More inparticular, stereogenic centers may have the R- or S-configuration, andactive ingredients containing one or more double bonds may have the E-or Z-configuration.

An interesting group of active ingredients are those as describedhereinabove provided that salbutamol, isosorbide 5-mononitrate,dihydroergotamine, vitamine B12, conjugated estrogens, acetyl salicylicacid, fluoride, miconazole and triamcinolone are not included.

Another interesting group of active ingredients are those as describedhereinabove provided that salbutamol, isosorbide 5-mononitrate,dihydroergotamine, vitamine B12, conjugated estrogens, acetyl salicylicacid, fluoride, miconazole, triamcinolone, acyclovir, lamotrigine andacetaminophen in combination with diphenhydramine are not included.

In view of the presence of one or more active ingredients, the presentinvention also relates to a hydrophilic controlled release formulationas described hereinabove for use as a medicine.

As described hereinabove, pregelatinized starch is comprised in thepresent formulation. Pregelatinized starch is a readily availableproduct, which can be manufactured by precooking and drying starches. Itis widely used in the food industry in order to give viscous pastesafter reconstitution in water.

Pregelatinization may be obtained by:

spray drying: pregelatinized starches produced in this way consist ofhollow spheres, usually with an air cell enclosed at the center. Theyare made by first cooking the starch in water and then by spraying thehot paste into a drying chamber or tower;

roll-drying: pregelatinized starches prepared in this way consist ofparticles appearing as transparant, flat irregular platelets. In generalthese products are simultaneously cooked and dried on heated rolls,using either a closely set pair of squeeze rolls or a single roll with aclosely set doctor blade. In either case, a paperthin flake, which isthen ground to mesh size, is obtained;

extrusion or drum-drying: pregelatinized starches prepared in this wayconsist of individual particles which are much thicker and moreirregular than roll-dried products. Drum-drying is similar toroll-drying except that a thicker coating of starch paste is applied tothe heated rolls, and the dried product is then ground to the desiredparticle size. In the extrusion process, moistened starch is forcedthrough a super heated chamber under very high shear, then exploded andsimultaneously dried by venting at atmospheric pressure.

A preferred form of pregelatinized starch is drum dried waxy maizestarch, which is available from the company Cerestar Benelux BV (Breda,the Netherlands).

The weight percentage of pregelatinized starch in the hydrophiliccontrolled release formulation of the present invention preferablyranges from about 0.01% to less than 80% (w/w), more preferably fromabout 0.01% to about 15%, even more preferably from about 0.01% to about5%, and most preferred is about 5%.

The hydrophilic polymers constituting the controlled release matrixpreferably release the active ingredient(s) gradually, slowly,continuously. They swell upon contact with aqueous fluid followingadministration, resulting in a viscous, drug release regulatinggellayer. The viscosity of the polymers preferably ranges from 150 to100,000 mPa.s (apparent viscosity of a 2% aqueous solution at 20° C.).Examples of such polymers are

alkylcelluloses, such as, methylcellulose;

hydroxyalkylcelluloses, for example, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose;

hydroxyalkyl alkylcelluloses, such as, hydroxyethyl methylcellulose andhydroxypropyl methylcellulose;

carboxyalkylcelluloses, such as, carboxymethylcellulose;

alkali metal salts of carboxyalkylcelluloses, such as, sodiumcarboxymethylcellulose;

carboxyalkylalkylcelluloses, such as, carboxymethylethylcellulose;

carboxyalkylcellulose esters;

other natural, semi-synthetic, or synthetic polysaccharides, such as,alginic acid, alkali metal and ammonium salts thereof, carrageenans,galactomannans, tragacanth, agar-agar, gummi arabicum, guar gummi,xanthan gummi, starches, pectins, such as sodiumcarboxymethylamylopectin, chitin derivates such as chitosan,polyfructans, inulin;

polyacrylic acids and the salts thereof;

polymethacrylic acids and the salts thereof, methacrylate copolymers;

polyvinylalcohol;

polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinylacetate;

combinations of polyvinylalcohol and polyvinylpyrrolidone;

polyalkylene oxides such as polyethylene oxide and polypropylene oxideand copolymers of ethylene oxide and propylene oxide.

Preferable hydrophilic polymers are polysaccharides, more in particularcellulose derivatives and most in particular cellulose etherderivatives.

Most preferred cellulose ether derivatives are hydroxypropylmethylcellulose and hydroxypropyl cellulose.

Different viscosity grades of hydroxypropyl cellulose and hydroxypropylmethylcellulose are commercially available.

Hydroxypropyl methylcellulose preferably used in the present inventionhas a viscosity grade ranging from about 3,500 mPa.s to about 100,000mPa.s, in particular ranging from about 4,000 mPa.s to about 20,000mPa.s and most in particular a viscosity grade of about 6,500 mPa.s toabout 15,000 mPa.s (apparent viscosity of a 2% aqueous solution at 20°C.), e.g. hypromellose 2208 (DOW, Antwerp, Belgium).

Hydroxypropyl cellulose having a viscosity lower than 1,500 mPa.s(apparent viscosity of a 2% aqueous solution at 20° C.) is preferred, inparticular hydroxypropyl cellulose having a viscosity in the range fromabout 150 to about 700 mPa.s, preferably from 200 to 600 mPa.s, e.g.Klucel EFO (Hercules, Wilminton, USA).

The viscous hydrophilic polymers constituting the matrix mainly providefor the controlled pharmacokinetic release profile of the preparation.Depending on the amount of polymers processed in the preparation, therelease profile can be tuned. Preferably, the amount of viscoushydrophilic polymer in the present formulation ranges from about 0.01 toabout 80% (w/w). In addition, when using a combination of polymers, theratio of said polymers also influences the release profile of thepreparation. For example, when using one or more hydrophilic polymers,preferably cellulose derivatives, more in particular hydroxypropylcellulose and hydroxypropyl methylcellulose, the weight percentage (%w/w) of hydroxypropyl methylcellulose preferably ranges from 0 to about16%; the weight percentage of hydroxypropyl cellulose preferably rangesbetween about 25% and about 62%. The ratio of hydroxypropyl cellulose tohydroxypropyl methylcellulose preferably ranges from 1:5 to 5:1, morepreferable from 1:1 to 5:1, and most preferred from 3:1 to 5:1.

A combination of different polymers offers the possibility of combiningdifferent mechanisms by which the active ingredient(s) is (are) releasedfrom the matrix. Such combination facilitates control of thepharmacokinetic release profile of the preparation at will. As mentionedhereinabove, three main mechanisms exist by which an active ingredientcan be released from a hydrophilic matrix: dissolution, erosion anddiffusion. An active ingredient will be released by the dissolutionmechanism when it is homogeneously dispersed in a matrix network of asoluble polymer. The network will gradually dissolve in thegastrointestinal tract, thereby gradually releasing its load. The matrixpolymer can also gradually be eroded from the matrix surface, likewisereleasing the active ingredient in time. When an active ingredient isprocessed in a matrix made up of an insoluble polymer, it will bereleased by diffusion: the gastro-intestinal fluids penetrate theinsoluble, sponge-like matrix and diffuse back out loaded with drug.

Release of one or more active ingredients from a matrix containinghydroxypropyl cellulose and hydroxypropyl methylcellulose occurs by acombined set of release mechanisms. Due to the higher solubility ofhydroxypropyl methylcellulose compared with hydroxypropyl cellulose, theformer will gradually dissolve and erode from the matrix, whereas thelatter will more act as a sponge-like matrix former releasing the activeingredient mainly by diffusion.

Beside active ingredient(s), hydrophilic polymers and pregelatinizedstarch, the formulation of the present invention may also optionallycomprise pharmaceutically acceptable formulating agents in order topromote the manufacture, compressibility, appearance and taste of thepreparation. These formulating agents comprise, for example, diluents orfillers, glidants, binding agents, granulating agents, anti-cakingagents, lubricants, flavors, dyes and preservatives.

The filler may be selected from soluble fillers, for example, sucrose,lactose, trehalose, maltose, mannitol, sorbitol, inulin, and frominsoluble fillers, for example, dicalcium or tricalcium phosphate, talc.An interesting filler is lactose, in particular, lactose monohydrate.Different grades of lactose can be used. One type of lactose preferablyused in the present invention is lactose monohydrate 200 mesh (DMV,Veghel, the Netherlands). Another lactose monohydrate, lactosemonohydrate of the type DCL 11 (DMV, Veghel, the Netherlands), can alsopreferably be used. The notation DCL refers to “Direct CompressionLactose”. The number 11 is a reference number of the manufacturer. Thistype of lactose is characterised in that 98% (w/w) of the particles havea diameter smaller than 250 μm, 30% (w/w) to 60% (w/w) of the particleshave a diameter of 100 μm and at maximum 15% (w/w) of the particles havea diameter of smaller than 45 μm.

The weight percentage of filler ranges between about 6% and about 54%(w/w).

Among the optional formulating agents that further may be comprised inthe matrix formulation there may be mentioned agents such as polyvidone;starch; acacia gum; gelatin; seaweed derivatives, e.g. alginic acid,sodium and calcium alginate; cellulose derivatives, e.g. ethylcellulose,hydroxypropylmethylcellulose, having useful binding and granulatingproperties; glidants such as colloidal silica, starch or talc;lubricants such as magnesium stearate and/or palmitate, calciumstearate, stearic acid, polyethylene glycol, liquid paraffin, sodium ormagnesium lauryl sulphate; antiadherents such as talc and corn starch.

In addition to the pharmaceutical acceptable formulating agentsdescribed above, cyclodextrins or derivatives thereof may also beincluded in the present controlled release formulation to improve thedissolution rate of the active ingredient(s). For this purpose, therecommended amount of cyclodextrin or derivatives thereof may replace anequivalent amount of filler.

Drug release from an oral solid controlled release dosage form andsubsequent absorption of the drug from the gastro-intestinal tract intothe blood stream is dissolution-rate dependent and can be slow andirregular especially in case of a sparingly water soluble, a slightlywater soluble, a very slightly water soluble, a practically waterinsoluble or a water insoluble drug, defined according to the UnitedStates Pharmacopeia 24, p 10.

In case of a drug with a pH dependent solubility, the release of thedrug from the dosage form and subsequent the absorption into the bloodstream can vary during the passage of the dosage form along thegastro-intestinal tract. This is especially relevant for an alkalinedrug exhibiting a decreasing solubility with increasing pH. When passingalong the gastro-intestinal tract, the controlled release formulationwill reside for a substantial period of time in the lower part of thetract (ileum and colon) where the average pH value of the luminalcontent varies from 7.5 (ileum) over 6.4 (right colon) to 7.0 (leftcolon) (Evans et al., Gut, 29, 1035-1041, 1988; Wilson and Washington,in Physiological Pharmaceutics, Ellis Horwood Limited, West Sussex, UK,pp. 21-36, 1989). This higher pH value in the lower part of thegastro-intestinal tract, when compared with the upper part, may cause adecrease in solubility of the alkaline drug resulting in a lower drugrelease from the dosage form and hence a lower and slower drugabsorption.

Cyclodextrins or derivatives thereof are generally known as complexingagents. By incorporating a drug/cyclodextrin complex into the controlledrelease formulation of the present invention, the dissolution rate andsubsequently the absorption characteristics of sparingly water soluble,slightly water soluble, very slightly water soluble, practically waterinsoluble or water insoluble drugs or drugs having a pH dependentsolubility can be improved. In particular, it provides for a faster ormore regular release of said drugs; preferably a zero-order release isobtained. Beside the dissolution-rate enhancing function, thecyclodextrin or derivatives thereof may also act as an eroding elementof the present formulation.

The cyclodextrin to be used in the present invention includes thepharmaceutically acceptable unsubstituted and substituted cyclodextrinsknown in the art, more particularly α, β or γ cyclodextrins or thepharmaceutically acceptable derivatives thereof.

Substituted cyclodextrins which can be used in the invention includepolyethers described in U.S. Pat. No. 3,459,731. In general,unsubstituted cyclodextrins are reacted with an alkylene oxide,preferably under superatmospheric pressure and at an elevatedtemperature, in the presence of an alkaline catalyst. Since a hydroxymoiety of the cyclodextrin can be substituted by an alkylene oxide whichitself can react with yet another molecule of alkylene oxide, theaverage molar substitution (MS) is used as a measure of the averagenumber of moles of the substituting agent per glucose unit. The MS canbe greater than 3 and theoretically has no limit.

Further substituted cyclodextrins are ethers wherein the hydrogen of oneor more cyclodextrin hydroxy groups is replaced by C₁₋₆alkyl,hydroxyC₁₋₆alkyl, carboxyC₁₋₆alkyl or C₁₋₆alkyloxycarbonylC₁₋₆alkyl ormixed ethers thereof. In particular such substituted cyclodextrins areethers wherein the hydrogen of one or more cyclodextrin hydroxy groupsis replaced by C₁₋₃alkyl, hydroxyC₂₋₄alkyl or carboxyC₁₋₂alkyl or, morein particular, by methyl, ethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl, carboxymethyl or carboxy-ethyl.

In the foregoing definitions the term “C₁₋₂alkyl” is meant to includesaturated hydrocarbon radicals having 1 or 2 carbon atoms, such asmethyl or ethyl; the term “C₁₋₃alkyl” is meant to include straight andbranched chain saturated hydrocarbon radicals, having from 1 to 3 carbonatoms, including those described for the term “C₁₋₂alkyl” and1-methylethyl, propyl; the term “C₂₋₄alkyl” is meant to include straightand branched chain saturated hydrocarbon radicals, having from 2 to 4carbon atoms, including ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl,2-methylpropyl, butyl, and the like; the term “C₁₋₆alkyl” is meant toinclude straight and branched chain saturated hydrocarbon radicals,having from 1 to 6 carbon atoms, including those described for the termsmentioned hereinbefore and pentyl, hexyl and the like.

Such ethers can be prepared by reacting the starting cyclodextrin withan appropriate O-alkylating agent or a mixture of such agents in aconcentration being selected so that the desired cyclodextrin ether isobtained. The said reaction is preferably conducted in a suitablesolvent in the presence of an appropriate base. With such ethers, thedegree of substitution (DS) is the average number of substituted hydroxyfunctions per glucose unit, the DS being thus 3 or less.

In the cyclodextrin derivatives for use in the formulation according tothe present invention, the DS preferably is in the range of 0.125 to 3,in particular 0.3 to 2, more in particular 0.3 to 1 and the MS is in therange of 0.125 to 10, in particular of 0.3 to 3 and more in particular0.3 to 1.5.

Of particular utility in the present invention are the β-cyclodextrinethers, e.g. dimethyl-β-cyclodextrin as described in Drugs of theFuture, Vol. 9, No. 8, p. 577-578 by M. Nogradi (1984) and polyethers,e.g. hydroxypropyl β-cyclodextrin and hydroxyethyl β-cyclodextrin, beingexamples. Such an alkyl ether may be a methyl ether with a degree ofsubstitution of about 0.125 to 3, e.g. about 0.3 to 2. Such ahydroxypropyl cyclodextrin may for example be formed from the reactionbetween β-cyclodextrin an propylene oxide and may have a MS value ofabout 0.125 to 10, e.g. about 0.3 to 3.

Another suitable type of substituted cyclodextrins issulfobutylcyclodextrins. This type is also envisaged in the presentinvention.

The cyclodextrin preferably being used in the present invention isβ-cyclodextrin, and more in particular hydroxypropyl β-cyclodextrin,because of its higher water solubility.

The ratio of cyclodextrin over active ingredient may vary widely. Itdepends on the active ingredient or the cyclodextrin being used, thedesired dissolution profile, the solubility of the cyclodextrin andactive ingredient in the solvent used to prepare the cyclodextrin-activeingredient mixture, as described hereinafter. Preferably, ratio's of atleast 1:1 may be applied, although lower ratio's are not excluded.

The use of a mixture of cyclodextrins, either different types (α, β, γ)or different substitutions (2-hydroxypropyl or methyl) or differentsubstitution grades is also envisaged in the present invention.

To incorporate the cyclodextrins or derivatives thereof in the presentcontrolled release formulation, the cyclodextrin is preferably firstintimately mixed with the active ingredient(s), followed by mixing thisintimate mixture with the remaining components of the controlled releaseformulation.

Different techniques can be used to prepare the intimate mixture of thecyclodextrin and the active ingredient(s), comprising

a) a simple mixing technique wherein the two components are physicallymixed in a suitable mixing apparatus, e.g. a Turbula mixer (Willy A.Bachoven Machinenfabrik, Bazel, Swiss);

b) a ball-milling technique wherein the two components are broughttogether and milled in a suitable ball-mill (Retsch GMBH & Co, Haan,Germany);

c) a dry compaction technique wherein the cyclodextrin and the activeingredient(s) are mixed in a suitable mixing apparatus. The resultingmixture is then run through a compactor, e.g. a Polygran 3W compactor(Gerteis, Jona, Swiss), followed by breaking down the resultingagglomerates, e.g. sheets or plates.

d) a solid dispersion technique. The term “a solid dispersion” usedhereinafter defines a system in a solid state (as opposed to a liquid orgaseous state) comprising at least two components, in casu the activeingredient(s) and the cyclodextrin, wherein one component is dispersedmore or less evenly throughout the other component or components (incase additional pharmaceutically acceptable formulating agents,generally known in the art, are included, such as plasticizers,preservatives and the like). When said dispersion of the components issuch that the system is chemically and physically uniform or homogenousthroughout or consists of one phase as defined in thermo-dynamics, sucha solid dispersion will be called “a solid solution” hereinafter. Solidsolutions are preferred physical systems because the components thereinare usually readily bioavailable to the organisms to which they areadministered.

This advantage can probably be explained by the ease with which saidsolid solutions can form liquid solutions when contacted with a liquidmedium such as the gastro-intestinal juices. The ease of dissolution maybe attributed at least in part to the fact that the energy required fordissolution of the components from a solid solution is less than thatrequired for the dissolution of components from a crystalline ormicrocrystalline solid phase.

The term “a solid dispersion” also comprises dispersions which are lesshomogenous throughout than solid solutions. Such dispersions are notchemically and physically uniform throughout or comprise more than onephase. For example, the term “a solid dispersion” also relates to asystem having domains or small regions wherein amorphous,microcrystalline or crystalline active ingredient(s), or amorphous,microcrystalline or crystalline cyclodextrin, or both, are dispersedmore or less evenly in another phase comprising cyclodextrin, or activeingredient(s), or a solid solution comprising active ingredient(s) andcyclodextrin. Said domains are regions within the solid dispersiondistinctively marked by some physical feature, small in size, and evenlyand randomly distributed throughout the solid dispersion.

Various techniques exist for preparing solid dispersions includingmelt-extrusion, spray-drying, freeze-drying and solution-evaporation,the latter technique being preferred.

The solution-evaporation process comprises the following steps:

a) dissolving the active ingredient(s) and the cyclodextrin in anappropriate solvent, such as water or an organic solvent, such as analcohol, e.g. methanol, ethanol, or mixtures thereof, optionally atelevated temperatures;

b) evaporating the solvent of the solution resulting under point a),optionally under vacuum. The solution may also be poured onto a largesurface so as to form a thin film, and evaporating the solventtherefrom.

In the spray-drying technique, the two components are also dissolved inan appropriate solvent and the resulting solution is then sprayedthrough the nozzle of a spray dryer followed by evaporating the solventfrom the resulting droplets at elevated temperatures.

In the freeze-drying technique, the cyclodextrin and the activeingredient(s) are dissolved in an appropriate solvent. This mixture isthen frozen followed by sublimating the solvent under vacuum and undersupply of heat of sublimation while continuously removing the vaporformed. The resulting freeze-dried solid may be subjected to a secondarydrying process at elevated temperature.

The melt-extrusion process comprises the following steps:

a) mixing the active ingredient(s) and the cyclodextrin,

b) optionally blending additives with the thus obtained mixture,

c) heating and compounding the thus obtained blend until one obtains ahomogeneous melt,

d) forcing the thus obtained melt through one or more nozzles; and

e) cooling the melt till it solidifies.

The terms “melt” and “melting” should be interpreted broadly. Theseterms not only mean the alteration from a solid state to a liquid state,but can also refer to a transition to a glassy state or a rubbery state,and in which it is possible for one component of the mixture to getembedded more or less homogeneously into the other. In particular cases,one component will melt and the other component(s) will dissolve in themelt thus forming a solution, which upon cooling may form a solidsolution having advantageous dissolution properties.

After preparing the solid dispersions as described hereinabove, theobtained products can be optionally milled and sieved.

It will be appreciated that a person of skill in the art will be able tooptimize the parameters of the techniques for the preparation of theintimate mixture of active ingredient(s) and cyclodextrin describedabove, such as the most appropriate solvent, the working temperature,the kind of apparatus being used, the rate of mixing and milling, therate of spray-drying, the freezing rate, the sublimation rate, thethroughput rate in the melt-extruder and the like.

Instead of cyclodextrins or derivatives thereof other water-solublepolymers may be used to prepare the above described intimate mixturewith the active ingredient(s). Suitable water-soluble polymers have anapparent viscosity, when dissolved at 20° C. in an aqueous solution at2% (w/v), of 1 to 5000 mPa.s more preferably of 1 to 700 mPa.s, and mostpreferred of 1 to 100 mPa.s. For example, the water-soluble polymer canbe selected from the group comprising

alkylcelluloses such as methylcellulose,

hydroxyalkylcelluloses such as hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose,

hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose andhydroxypropyl methylcellulose,

carboxyalkylcelluloses such as carboxymethylcellulose,

alkali metal salts of carboxyalkylcelluloses such as sodiumcarboxymethylcellulose,

carboxyalkylalkylcelluloses such as carboxymethylethylcellulose,

carboxyalkylcellulose esters,

starches,

pectines such as sodium carboxymethylamylopectine,

chitin derivates such as chitosan,

di-, oligo- and polysaccharides such as trehalose, alginic acid, alkalimetal and ammonium salts thereof, carrageenans, galactomannans,tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi,

polyacrylic acids and the salts thereof,

polymethacrylic acids, the salts and esters thereof, methacrylatecopolymers,

polyvinylalcohol,

polyvinylpyrrolidone, polyvinylpyrrolidone-vinylacetate copolymers,

combinations of polyvinylpyrrolidone and polyvinylalcohol,

polyalkylene oxides such as polyethylene oxide and polypropylene oxideand copolymers of ethylene oxide and propylene oxide.

An interesting formulation according to the present invention is: Activeingredient(s) 0.01-50% (w/w) Viscous hydrophilic polymer(s) 0.01-80%(w/w) Pregelatinized starch 0.01-<80% (w/w) Pharmaceutically acceptableformulating agents ad 100% (w/w). or Active ingredient(s) 0.01-50% (w/w)Viscous hydrophilic polymer(s) comprising 0.01-80% (w/w) hydroxypropylcellulose Pregelatinized starch 0.01-<80% (w/w) Pharmaceuticallyacceptable formulating agents ad 100% (w/w). Another interestingformulation according to the present invention is: Active ingredient(s)0.01-50% (w/w) Viscous hydrophilic polymer(s) 0.01-80% (w/w)Pregelatinized starch 0.01-15% (w/w) Pharmaceutically acceptableformulating agents ad 100% (w/w). or Active ingredient(s) 0.01-50% (w/w)Viscous hydrophilic polymer(s) comprising 0.01-80% (w/w) hydroxypropylcellulose Pregelatinized starch 0.01-15% (w/w) Pharmaceuticallyacceptable formulating agents ad 100% (w/w). Yet another interestingformulation according to the present invention is: Active ingredient(s)0.01-50% (w/w) Viscous hydrophilic polymer(s) 0.01-80% (w/w)Pregelatinized starch 0.01-5% (w/w) Pharmaceutically acceptableformulating agents ad 100% (w/w). or Active ingredient(s) 0.01-50% (w/w)Viscous hydrophilic polymer(s) comprising 0.01-80% (w/w) hydroxypropylcellulose Pregelatinized starch 0.01-5% (w/w) Pharmaceuticallyacceptable formulating agents ad 100% (w/w). Still another interestingformulation according to the present invention is: Active ingredient(s)0.01-50% (w/w) Hydroxypropyl cellulose 25-62% (w/w) Hydroxypropylmethylcellulose 0-16% (w/w) Pregelatinized starch 0.01 to 5% (w/w)Pharmaceutically acceptable formulating agents ad 100% (w/w).

The controlled release matrix formulation of the present invention isgenerally prepared according to the following process:

(1.a) one or more active ingredients, pregelatinized starch, one or moreviscous hydrophilic polymers and optionally some or all of thepharmaceutically acceptable formulating agents are mixed;

(1.b) the powder mixture prepared under (1.a) is run through acompactor, thus yielding plates;

(1.c) the resulting plates are broken down and sieved, thus yieldinggranules;

(1.d) the resulting granules are optionally mixed with all or theremainder of the pharmaceutically acceptable formulating agents untilhomogeneous.

In case the active ingredient(s) is a sparingly water soluble, slightlywater soluble, very slightly water soluble, practically water insolubleor water insoluble drug or a drug with a pH dependent solubility, inparticular an alkaline drug, the active ingredient(s) may beincorporated in the controlled release formulation as an intimatemixture with a cyclodextrin or derivatives thereof or another watersoluble polymer, as described hereinabove. In said case, the preparationof the present controlled release formulation comprises an additionalfirst step, namely

(2.a) one or more active ingredients and the water soluble polymer areintimately mixed;

(2.b) the intimate mixture prepared under (2.a) is mixed withpregelatinized starch, one or more viscous hydrophilic polymers andoptionally some or all of the pharmaceutically acceptable formulatingagents;

(2.c) the powder mixture prepared under (2.b) is run through acompactor, thus yielding plates;

(2.d) the resulting plates are broken down and sieved, thus yieldinggranules;

(2.e) the resulting granules are optionally mixed with all or theremainder of the pharmaceutically acceptable formulating agents untilhomogeneous.

The formulation obtained by the processes as described hereinabove maybe used for the manufacture of a dosage form, in particular a controlledrelease dosage form. A preferred dosage form is a solid dosage form, inparticular an oral solid dosage form and more in particular a tablet ora capsule, e.g. a capsule filed with pellets obtained from theformulation of the present invention. Said tablet may be obtained bytabletting in an art-known tabletting machine the final blend resultingfrom the above described processes, i.e. the blend resulting under (1.d)or (2.e).

A compactor as mentioned in step (1.b) or (2.c) of the above describedprocesses is an apparatus wherein the powdery mixture is run between tworollers exerting pressure on the powdery mixture. In this way themixture is compacted and sheets or plates are formed. Compactors arecommercially available, for instance, from the company Gerteis (Jona,Swiss), e.g. a Polygran 3W compactor.

The above general route of preparation of the controlled releaseformulation may be modified by a person skilled in the art by forinstance adding certain ingredients at other stages than indicatedabove.

As an alternative to the above described route of preparation involvinga compaction step, the above described mixture can also be tablettedusing direct compression. When using the technique of directcompression, dies or matrices in the form of the desired tablets arefilled with a powdery mixture having the tablet composition and then arepunched. The advantage of this way of tabletting is that it usuallyrequires less steps. Apparatuses for direct compression tabletting arecommercially available. These apparatuses require forced feeding systemswhenever the rheological properties of the mixture are not appropriateto fill the dies or matrices without forced feeding.

The resulting tablets may have different kinds of shapes, e.g. oblong orcircular. A person skilled in the art will appreciate that the shape ofthe tablet influences the release period, because of the fact thatdifferent shapes have a different ratio of surface to volume.Consequently, in view of the fact that the dissolution of a tablet is aprocess that mainly takes place at the surface of the tablet, adifferent shape can mean-but not necessarily-a different dissolutionprofile.

The resulting tablets may also have different nominal weights and thusdifferent sizes. The size of the tablet affects the surface to volumeratio, and consequently influences the release period, as mentionedhereinabove.

The resulting tablets are manufactured from a homogeneous dispersion ofthe hereinabove mentioned ingredients. Said dispersion may be obtainedby physically mixing the ingredients. The controlled release profile ofthe tablets is established by the formation of a gellayer due to theswelling of the homogeneously dispersed hydrophilic polymers. Thisimplies that the tablets are dividable and may be provided with asuitable score. This allows one to adjust the recommended dose wheneverrequired.

The above described ingredients, ratios and weight percentages apply foruncoated tablets or for tablet cores, i.e. the tablet without thecoating.

However, the tablets of the present invention are preferably film coatedwith art-known film coating compositions. The coating is applied toimprove the aspect and/or the taste of the tablets and the ease withwhich they can be swallowed. Coating the tablets of the presentinvention may also serve other purposes, e.g. improving stability andshelf-life.

Suitable coating formulations comprise a filmforming polymer such as,for example, hydroxypropyl methylcellulose, e.g. hypromellose 2910 (5mPa.s), a plasticizer such as, for example, a glycol, e.g. propyleneglycol or polyethylene glycol, an opacifier, such as, for example,titanium dioxide, and a film smoothener, such as, for example, talc.

Suitable coating solvents are water as well as organic solvents.Examples of organic solvents are alcohols, e.g. ethanol or isopropanol,ketones, e.g. acetone, or halogenated hydrocarbons, e.g. methylenechloride.

Optionally, the coating may contain a therapeutically effective amountof one or more active ingredients to provide for an immediate release ofsaid active ingredient(s) and thus for an immediate relief of thesymptoms treated by said active ingredient(s).

Coated tablets of the present invention are prepared by first making thetablet cores in the way as described above and subsequently coating saidtablet cores using conventional techniques, such as coating in a coatingpan.

The active ingredient(s) is (are) present in the dosage form preparedfrom the formulation of the present invention in a therapeuticallyeffective amount. The amount that constitutes a therapeuticallyeffective amount varies according to the ingredients being used, thecondition being treated, the severity of said condition, and the patientbeing treated. The amount of active ingredient(s) used in the presentinvention preferably ranges between about 0.01% and about 50% (w/w).

The following examples are intended to illustrate the present invention.

Experimental Part

Tablet formulations Tablet 1 Cisapride-(L)-tartrate 52.92 mg Lactosemonohydrate 200 mesh 274.83 mg Hydroxypropyl methylcellulose 2208 34.2mg Hydroxypropyl cellulose 142.5 mg Drum dried waxy maize starch 28.5 mgMagnesium stearate 2.85 mg Colloidal anhydrous silica 5.7 mg Talc* 28.5mg Tablet 2 Cisapride-(L)-tartrate 52.92 mg Lactose monohydrate 200 mesh149.43 mg Hydroxypropyl methylcellulose 2208 74.1 mg Hydroxypropylcellulose 228.00 mg Drum dried waxy maize starch 28.5 mg Magnesiumstearate 2.85 mg Colloidal anhydrous silica 5.7 mg Talc* 28.5 mg Tablet3 3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]- 16.00 mg2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one microfine Lactose monohydrateDCL11 108.80 mg Hydroxypropyl methylcellulose 2208 41.60 mgHydroxypropyl cellulose 128.00 mg Drum dried waxy maize starch 16.00 mgMagnesium stearate 6.4 mg Colloidal anhydrous silica 3.20 mg Tablet 43-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H-yl]ethyl]- 16.00 mg2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one microfine Lactose monohydrateDCL11 54.20 mg Hydroxypropyl methylcellulose 2208 23.40 mg Hydroxypropylcellulose 72.00 mg Drum dried waxy maize starch 9.00 mg Magnesiumstearate 3.6 mg Colloidal anhydrous silica 1.80 mg Tablet 53-[2-(3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl)ethyl]- 21.26 mg2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one butanedioate(1:1) Lactosemonohydrate DCL11 103.54 mg Hydroxypropyl methylcellulose 2208 41.60 mgHydroxypropyl cellulose 128.00 mg Drum dried waxy maize starch 16.00 mgMagnesium stearate 6.4 mg Colloidal anhydrous silica 3.20 mg Tablet 63-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]- 16 mg2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one microfine Hydroxypropylβ-cyclodextrin 200 mg Lactose monohydrate DCL11 6.3 mg Hydroxypropylmethylcellulose 2208 74.1 mg Hydroxypropyl cellulose 228 mg Drum driedwaxy maize starch 28.5 mg Magnesium stearate 11.4 mg Colloidal anhydroussilica 5.7 mg Ethanol 96% (v/v)** 363 mg *During upscaling of theproduction process, talc may be replaced by magnesium stearate andlactose monohydrate DCL 11 because of technological reasons. **does notappear in the final product.

Preparation of Tablet 1 to 5

The active ingredient, hydroxypropyl methylcellulose, hydroxypropylcellulose, drum dried waxy maize starch and, in case lactose monohydrate200 mesh was used (Tablets 1 and 2), the lactose filler, were mixed in aplanetary mixer, and than compacted using a dry compactor. The compactwas broken down, sieved and mixed in a planetary mixer with colloidalanhydrous silica and, in case lactose monohydrate DCL 11 was used(Tablets 3, 4 and 5), the lactose filler. Magnesium stearate was addedand mixed. The resulting blend was tabletted using an excentric press.From the above described tablet preparation procedure, it can beconcluded that the lactose filler may be added before or after drycompaction of the polymer blend. This depends on the kind of lactoseused, more in particular on the particle size of the lactose.

Preparation of Tablet 6

The active ingredient and hydroxypropyl β-cyclodextrin were dissolved inethanol 96% (v/v) at 75° C. The resulting solution was evaporated tilldry under vacuum. The resulting precipitate was milled and sieved andsubsequently mixed with hydroxypropyl methylcellulose, hydroxypropylcellulose and drum dried waxy maize starch in a planetary mixer, andthan compacted using a dry compactor. The compact was broken down,sieved and mixed with colloidal anhydrous silica and lactose in aplanetary mixer. Magnesium stearate was added and mixed. The resultingblend was tabletted using an excentric press.

Coating Preparation

A coating solution was prepared by mixing 69.0% w/w of methylenechloride with 17.30% w/w of ethanol 96% v/v and suspending therein 6.0%w/w of hydroxypropyl methylcellulose 2910 5mPa.s, 1.5% w/w ofpolyethylene glycol 400, 4.0% w/w of talc, 1.5% w/w of titanium dioxideand 0.60% w/w of polyethylene glycol 6000. This coating suspension wasapplied to tablets 3 and 4 in a coating pan, resulting in a coatingthickness of 42.8 mg/tablet 3 and 28.4 mg/tablet 4. Optionally, one ormore active ingredients can be incorporated in said coating suspension.

In vitro Dissolution Assay

a) Cisapride-(L)-tartrate release from tablet 1 and tablet 2 wasassessed in vitro at 37° C. by placing each tablet in a beakercontaining 400 ml of pH 7.2 McIlvaine buffer or Eurand buffer with 1.5%sodium lauryl sulfate. The medium was stirred with a paddle at 150revolutions per minute. After 2 hours, 600 ml of buffer (McIlvaine orEurand) was added to the dissolution medium and the stirring rate wasreduced to 100 revolutions per minute. At appropriate time intervals,samples were taken from the release medium and analyzed via UVspectrometry.

A McIlvaine buffer solution (100 ml) (J. Biol. Chem. 49, 183 (1921)) ofpH 7.2 consists of 13.05 ml of a citric acid solution (0.1 M) and 86.95ml of a Na₂HPO₄.2H₂O solution (0.2 M). This McIlvaine buffer solutionhas a higher ionic strength than the

Eurand buffer solution in which dissolution tests are normallyperformed. At pH 7.2 the ionic strength of a McIlvaine buffer is 0.398.

An Eurand buffer solution (100 ml) of pH 7.2 consists of 190 ml of asodium hydroxide solution (0.2 N) and 0.087 g of KH₂PO₄. The pH of thesolution is adjusted to 7.2 with hydrochloric acid 1N and diluted to 100ml with water. The ionic strength of this Eurand buffer pH 7.2 is 0.076.

Table 1 shows the percentage of cisapride-(L)-tartrate released ineither McIlvaine or Eurand buffer as a function of time for tablet 1 andtablet 2. The data illustrate that controlled release of the activeingredient from the tablets is not impeded when the ionic strength ofthe release medium is increased. They also show that by adapting theamount of hydroxypropyl cellulose and hydroxypropyl methylcellulose, therelease profile can be tuned.

b)3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-onerelease from tablet 3 and tablet 4, both tablets coated as describedhereinabove under “Coating preparation”, was assessed in vitro at 37° C.by placing each tablet in a basket in a beaker containing 900 ml of 0.1N HCl. The medium was stirred with the basket at 100 revolutions perminute. At appropriate time intervals, samples were taken from therelease medium and analyzed via UV spectrometry.

Table 2 shows the percentage of3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]-ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-onereleased as a function of time for coated tablet 3 and coated tablet 4.The data illustrate the controlled release of the active ingredient fromthe tablets and also show that by adapting the nominal weight and thussize of the tablet, the release profile can be tuned.

c) A tablet having the following composition was prepared:

Cisapride-(L)-tartrate 52.92 mg Lactose 346.08 mg Hydroxypropylmethylcellulose 2208 66.00 mg Hydroxypropyl cellulose 67.95 mg Magnesiumstearate 2.85 mg Colloidal anhydrous silica 5.70 mg Talc 28.60 mg.

The release of cisapride-(L)-tartrate was assessed in vitro at 37° C. byplacing the tablet in a basket in a beaker containing 400 ml of pH 7.2McIlvaine buffer with 1.5% sodium lauryl sulfate. The medium was stirredwith the basket at 150 revolutions per minute. At appropriate timeintervals, samples were taken from the release medium and analyzed viaUV spectrometry.

Table 3 shows the percentage of cisapride-(L)-tartrate released as afunction of time. The data illustrate that the active ingredient isreleased very fast. The formulation lacking the pregelatinized starchwas not able to provide a controlled release of the active drugsubstance; the tablet was not able to gel in the dissolution medium andform an integer matrix network. Instead it disintegrated within a timeinterval of about 10 to 15 min after immersion in the dissolutionmedium.

d) The dissolution of3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-onefrom the intimate mixture with hydroxypropyl β-cyclodextrin, prepared asdescribed in the Tablet 6 preparation procedure, was assessed in vitroat 37° C. by introducing 216 mg of said intimate mixture in a beakercontaining 300 ml of a pH 7.5 USP buffer. The medium was stirred with apaddle at 100 revolutions per minute. At appropriate time intervals,samples were taken from the dissolution medium and analyzed via UVspectrometry.

USP buffer pH 7.5 was prepared by bringing 6.805 g of KH₂PO₄, 204.5 mlof a 0.2 N NaOH solution and 700 ml of distilled water in a 1 literbeaker. After complete dissolution while stirring, the resulting mixtureis brought to a volume of 1 liter with distilled water in an appropriaterecipient.

Table 4 shows the percentage dissolved3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneas a function of time. The data illustrate that the dissolution of thealkaline active ingredient from the intimate mixture with hydroxypropylβ-cyclodextrin is fast in a medium of pH 7.5.

e)3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-onerelease from tablet 6 was assessed in vitro at 37° C. by placing thetablet in a basket in a beaker containing 600 ml of USP buffer pH 7.5.The medium was stirred with the basket at 100 revolutions per minute. Atappropriate time intervals, samples were taken from the release mediumand analyzed via UV spectrometry.

Table 5 shows the percentage of3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-onereleased in the USP buffer pH 7.5 as a function of time. The releaseprofile is that of a controlled and regular (zero order) release.

Clinical Trials Clinical Trial 1

The study described in this example aimed at evaluating and comparingthe bioavailability and pharmacokinetics of cisapride after the intakeof:

a single dose of 40 mg cisapride (administered ascisapride-(L)-tartrate) in a controlled-release formulation describedunder tablet formulation 2;

a one-day q.i.d. regimen (4 daily intakes) of the regular marketed 10 mgtablet (Prepulsid®), containing cisapride monohydrate as activeingredient.

In addition, the effects of the concommitant intake of a high-fat mealon the pharmacokinetics of the controlled release formulation wasstudied.

This explorative trial was an open 3-arm trial in 20 healthy volunteers.Male and female healthy volunteers, aged between 18 and 45 years, wereincluded. The three treatment periods were separated by a washout periodof at least 4 days.

Each volunteer took, in a randomised cross-over order, tablet 2, bothwhile fasting and directly after a high-fat meal, and a one-day q.i.d.regimen of Prepulsid®. The latter served as the reference treatment andtablets were taken under “market conditions”, i.e. 15 minutes before themain meals and at bed time.

The high-caloric, high-fat meal consisted of three slices of wheatenbread, 15 gram of butter, one scrambled egg and 15 gram of bacon friedin 5 gram of butter, 70 gram of cheese, 150 ml of high fat milk and 150ml of orange juice (approx. 400 kJ; 70 g of fat; 30 g protein, 40 gcarbohydrate, 350 g water). The cisapride controlled-release tablet wastaken within 10 minutes after completing the meal.

Blood samples were drawn pre-dose and at regular time intervals until 48hours post-dosing.

The plasma concentrations of cisapride were determined by a validatedHPLC method. The cardiovascular and laboratory safety and thetolerability of the various treatments were evaluated.

The results of the trial demonstrate that all treatments were safe andwell-tolerated.

The detailed pharmnacokinetic results are presented in Table 6.

The relative bioavailability of cisapride after intake of tablet 2 underfasting conditions is similar to a one-day q.i.d. course of the regularPrepulsid® tablet. When taken with a high-fat meal, the pharmacokineticperformance of tablet 2 was comparable to the intake under fastingconditions.

Clinical Trial 2

A second explorative trial aimed at evaluating the relative steady-statebioavailability of the controlled-release formulation tablet 2 ascompared to a standard treatment with Prepulsid®.

In this 2-arm open study, 18 healthy volunteers took, in a randomisedcross-over order, a 6-day course of tablet 2 once daily, and themarketed 10 mg Prepulsid® tablet q.i.d.

All tablets were ingested 15 minutes before a meal (or at bedtime forthe fourth tablet of the q.i.d. regimen).

Blood samples were drawn on day 6, starting predose and at regular timeintervals until 48h after the morning intake. The plasma concentrationsof cisapride were determined by a validated HPLC method. Thecardiovascular and laboratory safety and the tolerability of the varioustreatments were evaluated.

The results of the trial demonstrate that both chronic treatments werewell tolerated and safe.

The detailed pharmacokinetic results are presented in Table 6. Steadystate was attained for both treatments. The relative steady-statebioavailability of cisapride after once-daily intake of tablet 2 wassimilar as compared to q.i.d. treatment with the regular Prepulsid®tablet.

TABLE 1 % released cisapride-(L)-tartrate Tablet 1 Tablet 2 Time (min)Eurand McIlvaine Eurand McIlvaine 0 0.00 0.00 0.00 0.00 30 8.74 22.464.89 9.09 60 15.40 37.75 10.69 14.26 90 22.40 48.11 16.27 18.52 12028.44 62.62 21.74 23.19 150 28.15 66.34 20.87 22.33 180 29.60 74.1022.60 24.15 210 31.43 82.83 24.24 27.12 240 32.89 92.23 26.16 31.05 27034.63 97.28 28.18 35.94 300 36.46 98.15 30.20 41.21 330 38.40 98.3532.41 46.29 360 40.33 98.35 34.62 51.85 390 42.46 98.44 36.93 57.98 42044.49 98.25 39.05 67.57 450 41.16 76.00 480 43.18 83.48 510 45.30 88.37540 47.32 90.95 570 49.34 92.58 600 51.36 94.21 630 53.38 95.46 66055.11 96.42 690 56.84 97.18 720 58.57 97.66 750 60.49 98.05 780 62.2298.24 810 64.05 98.33 840 65.69 98.53 870 67.32 98.81 900 69.15 98.91

TABLE 2 % released 3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one Time (min)Coated Tablet 3 Coated Tablet 4 0 0.00 0.00 30 12.59 15.00 60 21.0424.97 90 27.73 33.46 120 33.72 41.44 150 39.37 48.64 180 44.84 55.29 21049.76 61.29 240 54.63 67.24 270 59.33 72.36 300 63.56 77.12 330 67.4081.64 360 70.98 85.66 390 74.34 89.21 420 77.49 92.44 450 80.46 94.84480 83.05 96.92 510 85.51 98.72 540 87.75 99.96 570 89.78 100.84 60091.54 101.39 630 93.23 101.49 660 94.73 101.44 690 95.68 101.53 72096.63 101.39 750 97.11 101.44 780 97.36 101.49 810 97.45 101.58 84097.58 101.53 870 97.58 101.53 900 97.67 101.58

TABLE 3 Time (min) % released active ingredient 0 0.00 30 89.31 60 93.4490 94.19 120 93.81

TABLE 4 Time (min) % dissolved active ingredient 0 0.00 5 100.88 15101.44 30 101.63

TABLE 5 Time (min) % released active ingredient 0 0.00 30 7.98 60 11.9990 15.30 120 17.74 150 20.03 180 21.94 240 25.80 270 27.53 300 29.63 33031.20 360 33.26 390 34.13 420 35.96

TABLE 6 Pharmacokinetic data for tablet 2 Fasting Fed Steady statet_(max), h 9.6 ± 4.5 6.4 ± 3.2 4.2 ± 3.2 C_(max), ng/ml 59.3 ± 18.9 74.9± 17.5 85.9 ± 32.9 AUC_(24h), ng · h/ml 968 ± 293 1012 ± 242  1305 ± 541AUC_(48h), ng · h/ml 1286 ± 383  1288 ± 346  1798 ± 783  AUC_(∞), ng ·h/ml 1373 ± 401  1349 ± 363  1982 (simulated) Bioequivalence Fed versusFasting F_(rel) Cmax 1.26 F_(rel) AUC24h 1.05 F_(rel) AUC48h 1.00F_(rel) AUC_(∞) 0.98 Bioequivalence versus Reference (Prepulsid ®q.i.d.) F_(rel) Cmax 0.84 1.05 0.99 F_(rel) AUC_(24h) 0.89 0.93 0.97F_(rel) AUC_(48h) 0.93 0.93 1.03 F_(rel) AUC_(∞) 0.96 0.94 1.10

What is claimed is:
 1. A hydrophilic controlled release formulationcomprising pregelatinized starch, one or more active ingredients, one ormore viscous hydrophilic polymers and optionally pharmaceuticallyacceptable formulating agents characterized in that the pregelatinizedstarch enables the formulation to maintain a controlled release of theincorporated active ingredient(s) in release media with changing ionicstrength, provided that the active ingredient is not salbutamol sulfate,isosorbide 5-mononitrate, dihydroergotamine mono-methane-sulfonate,vitamine B12, a conjugated estrogen, acetyl salicylic acid, fluoride,miconazole nitrate, triamcinolone, acyclovir, lamotrigine, bisacodyl oracetaminophen in combination with diphenhydraniine hydrochloride andprovided that the formulation does not contain a peptide consisting ofat most 5 amino acids, said peptide having a protective group selectedfrom phenylazobenzyloxycarbonyl, N-methyl, t-butyloxycarbonyl,fluoroenylmethyloxycarbonyl or carbobenzoxy at the N-terminus.
 2. Aformulation according to claim 1 wherein the pregelatinized starchenables the formulation to maintain a controlled release of theincorporated active ingredient(s) along the entire gastro-intestinaltract both in fasted as well as in fed conditions.
 3. A hydrophiliccontrolled release formulation comprising pregelatinized starch, one ormore active ingredients, one or more viscous hydrophilic polymers andoptionally pharmaceutically acceptable formulating agents characterizedin that the pregelatinized starch prevents dose-dumping from saidformulation along the gastro-intestinal tract both in fasted as well asin fed conditions, provided that the active ingredient is not salbutamolsulfate, isosorbide 5-mononitrate, dihydroergotaminemono-methane-sulfonate, vitamine B12, a conjugated estrogen, acetylsalicylic acid, fluoride, miconazole nitrate, triamcinolone, acyclovir,lamotrigine, bisacodyl or acetaminophen in combination withdiphenhydramine hydrochloride and provided that the formulation does notcontain a peptide consisting of at most 5 amino acids, said peptidehaving a protective group selected from phenylazobenzyloxycarbonyl,N-methyl, t-butyloxycarbonyl, fluoroenylmethyloxycarbonyl orcarbobenzoxy at the N-terminus.
 4. A formulation according to claim 1, 2or 3 having the following composition: Active ingredient(s) 0.01-50%(w/w) Viscous hydrophilic polymer(s) 0.01-80% (w/w) Pregelatinizedstarch 0.01-<80% (w/w) Pharmaceutically acceptable formulating agents ad100% (w/w).


5. A formulation according to claim 4 wherein the viscous hydrophilicpolymer comprises hydroxypropyl cellulose.
 6. A formulation according toclaim 1, 2 or 3 further comprising a water soluble polymer asdissolution-rate enhancer.
 7. A formulation according to claim 6 whereinthe water soluble polymer is hydroxypropyl β-cyclodextrin.
 8. A dosageform comprising a therapeutically effective amount of a formulationaccording to claim 1, 2 or
 3. 9. A dosage form according to claim 8shaped as an optionally coated tablet.
 10. A process for preparing aformulation according to claim 1, 2, 3 or 6, characterized by: (a)optionally intimately mixing one or more active ingredients and a watersoluble polymer; (b) mixing one or more active ingredients or, if (a)was performed, mixing the intimate mixture prepared under (a) withpregelatinized starch, one or more viscous hydrophilic polymers andoptionally some or all of the pharmaceutically acceptable formulatingagents; (c) compacting the powder mixture prepared under (b) by runningit through a compactor, thus yielding plates; (d) breaking the resultingplates down, thus yielding granules; (e) optionally mixing the resultinggranules with all or the remainder of the pharmaceutically acceptableformulating agents until homogeneous.
 11. A method of preventingdose-dumping which comprises administering an effective amount of ahydrophilic controlled release formulation comprising pregelatinizedstarch, one or more active ingredients, and one or more viscoushydrophilic polymers, whereby a controlled release of activeingredient(s) from said formulation in release media with changing ionicstrength is maintained.
 12. A method of preventing dose-dumping whichcomprises administering an effective amount of a hydrophilic controlledrelease formulation comprising pregelatinized starch, one or more activeingredients, whereby the pregelatinized starch counters the impairingeffect of ionic strength of the release medium on the controlled releaseof active ingredient(s) from said formulation.
 13. The method of claim11 wherein the ionic strength of the release medium ranges up to 0.4.14. The method of claim 11 wherein the ionic strength of the releasemedium is that encountered along the entire gastro-intestinal tract bothin fasted as well as in fed conditions.
 15. The method of claim 11wherein the ionic strength of the release medium ranges from about 0.01to about 0.2.
 16. A formulation according to claim 1, 2 or 3 wherein theone or more active ingredients are incorporated in the formulation inthe form of a complex with cyclodextrin or a derivative thereof.
 17. Aformulation according to claim 1, 2 or 3 wherein pregelatinized starchis present in a concentration from about 0.01% to about 5% (w/w).